Aerosol generator

ABSTRACT

An aerosol generator for generating an aerosol from a fluid, comprising: a vibratable membrane ( 22 ) having a first side ( 24 ) for being in contact with the fluid and an opposite second side ( 25 ), the membrane having a plurality of through holes ( 26 ) penetrating the membrane in an extension direction (E) from the first side to the second side, whereby the fluid passes the through holes from the first side to the second side when the membrane is vibrated for generating the aerosol at the second side, each through hole ( 26 ) having along its extension direction (E) a smallest diameter (Ds), a larger diameter (DL) that is larger than the smallest diameter and defined by that diameter that is closest to triple, preferably twice said smallest diameter, each through hole having a nozzle portion ( 32 ) defined by that continuous portion of the through hole in the extension direction comprising the smallest diameter of the through hole and bordered by the larger diameter of the through hole, characterized in that the ratio of the total length of each through hole ( 26 ) in the extension direction to the length of a respective one of said nozzle portions ( 32 ) in the extension direction is at least (4), preferably at least (4.5) and most preferred equal to or larger than (5).

The present invention relates to an aerosol generator and in particularto an aerosol generator having a vibratable membrane with a plurality ofthrough holes comprising a nozzle portion. More particularly the presentinvention relates to an optimized nozzle portion.

Aerosol generators are mainly used for industrial, laboratorial, and/ormedical application, as well as in the field of consumer products butare not limited thereto. Especially the generation of efficient,reproducible and constant aerosol output for greater liquid volumes iscurrently insufficiently realized. In all applications which require aconstant output or dose over the complete aerosol generation cycle(process) and reproducible output during every application an optimizedaerosol generator is needed.

Aerosol generators having a vibratable membrane as described above anddefined in the preamble of claim 1 are known by WO 93/10910 A1. Thethrough holes defined in the vibratable membrane may be formed byelectroforming such as disclosed in WO 01/18280 A1or by means of a lasersource as described for example in WO 00/29167 A1. Other techniques are,however, as well conceivable.

Further, it might turn out in dose finding studies that relatively highamounts of compound need to be delivered to a user. Yet, some liquids(e.g. medical substances or compounds) may not be administered at highconcentration for different reasons. High concentration can be relatedto disadvantageous physico-chemical properties for the nebulization suchas high viscosity (Newtonian fluid or non-Newtonian fluid likethixotrope). Further factors may be surface tension, density, kind of afluid (solution or suspension), solubility or size of particles in theliquid (e.g. micro or nano suspension). A compound might not be solvablein high concentrations or more generally the liquid containing thecompound might not be able to carry high concentrations of the compound(i.e. solution, suspension or colloidal drug formulation for an aerosolapplication and/or inhalation therapy, like liposomes, proteins,anti-bodies, emulsions, surfactants, viral shells and/or two vectors).Thus, in the administration a relatively large volume of fluid,particularly liquid, needs to be emitted in form of the aerosol. Theliquid may contain substance or compounds, for example medical liquids,active substances, drugs or further compounds, such as for therapeutic,analytical and/or diagnostic applications. In standard aerosolgenerators, such as those mentioned in the above documents a relativelylarge period of time is required for emitting the entire liquidcontaining the compound in the form of an aerosol.

Such a long period of time, however, is perceived negative anduncomfortable by a user which can lead to a lower acceptance of theapplication (e.g. medical aerosol therapy, compromised patientcompliance, potentially reduced efficacy of the medical aerosol therapyas well as print or fragrance aerosol applications).

Accordingly, the present invention aims to improve the known aerosolgenerators in this regard and to provide an aerosol generator thatenables the emission of even constant large amounts of fluid,particularly liquid in the form of an aerosol in a shorter period oftime.

This objective is resolved by an aerosol generator having the featuresas defined in claim 1. Embodiments of the present invention are definedin the dependent claims.

The present invention is based on the finding that the length of thenozzle portion of the through holes formed in the vibratable membranehas a significant influence on the total output rate (TOR) of the aboveaerosol generators. In particular, it has been found that the length ofthe nozzle portion is directly proportional to the total output rate,wherein the shorter the nozzle portion, the higher the TOR and viceversa. In contrast, it has been found that the diameter and the lengthof the portions upstream of the nozzle portion within the through holedo not have a significant influence on the TOR, if the nozzle portion issufficiently short and small in diameter as compared to the upstreamportion of the through hole. On the other hand, it has as well beenfound that the length of the nozzle portion as well has an influence onthe geometric standard deviation (GSD) of the droplet size distribution.Low GSDs characterize a narrow droplet size distribution (homogeneouslysized droplets), which is advantageous for targeting aerosol to therespiratory system. That is, the longer the nozzle portion the lower theGSD. The particle size (preferable below 5 μm) has a GSD in a range of2.2 to 1.5.

In view of the above findings, the present invention suggests an aerosolgenerator for generating an aerosol particularly a medical aerosol, froma fluid, preferably a liquid. The aerosol generator comprises avibratable membrane having a first side for being in contact with thefluid and an opposite second side, from which the droplets emerge. Themembrane may be vibrated by means of a piezoelectric actuator or anyother suitable means. The membrane has a plurality of through holespenetrating the membrane in an extension direction from the first sideto the second side. The through holes may be formed as previouslymentioned by a laser source, electroforming or any other suitableprocess. When the membrane is vibrating, the fluid passes the throughholes from the first side to the second side to generate the aerosol atthe second side. Each of the through holes has preferably an entranceopening and an exit opening, wherein a nozzle portion preferably extendsfrom the exit opening over a portion of the through holes towards theentrance opening. The nozzle portion is defined by that continuousportion of the through hole in the extension direction comprising asmallest diameter of the through hole and bordered by a larger diameterof the through hole. The larger diameter of the through hole is definedas that diameter that is closest to triple, preferably only twice thatsmallest diameter. The smallest diameter of the through hole maycorrespond to the exit opening. Based on the above findings, the aerosolgenerator of the present invention has through holes in which the ratioof the total length of each through hole in the extension direction tothe length of a respective one of said nozzle portions in the extensiondirection is at least 4, preferably at least 4.5 and most preferredequal to or larger than 5. In this context, at least 75%, morepreferably 90%, even more preferably 95% of the through holes need tofulfill the above ratio. Yet, due to manufacturing intolerances someholes may fall outside the range. It has been proven that a ratio below4, particularly when used in combination with high viscous fluids, highsurface tension or fluids having physico-chemical properties which leadto a reduced TOR, may lead to insufficient and reduced nebulization andthus lengthens the nebulization time. Further, it has been found that aratio of more than 10 will result in so-called bleeding. Bleeding inthis context means that fluid passes the membrane from the first side tothe second side even when the membrane is not vibrated. Thus, the secondside of the membrane is wetted with fluid or liquid beingcounterproductive for the nebulization process. Preferred upper limitsof the ratio are less than 8 and most preferred at about 6.5 or below.Further, it has been found that these ratios provide for an optimum ofan increased TOR and a reasonably low GSD. Thus, this configurationenables to achieve shorter application periods and thus comfort for thepatient and effectiveness of the medical compound. This is particularlyadvantageous if medical compounds are used which due to theirphysico-chemical properties lead to a reduced TOR or in which theconcentration of the active compound is limited so that a greater volumeof liquid containing the medical compound is to be administered.

According to one embodiment, it is preferred that the nozzle portionterminates flush with the second side. Hence, the length of the nozzleportion may be defined as that portion starting from the second sidetowards the first side up to and bordered by the diameter that it isclosest to triple, preferably twice the smallest diameter. The smallestdiameter will in these cases be located at the second side, as is theexit opening.

In any case, it is preferred that the smallest diameter, that is oneborder of the nozzle portion is located at that end of the nozzleportion in the extension direction adjacent to the second side and thatthe larger diameter of the through hole being the other border of thenozzle portion is located upstream of the smallest diameter in thedirection in which the fluid passes the through holes during operation.

According to one embodiment, it is preferred that the smallest diameteris smaller than 4.5 μm.

In addition, it is preferred that the total length of a through hole inthe extension direction is at least 50 μm, preferably at least 70 μm andmost preferred at least 90 μm.

The length of the nozzle portion is preferably less than 25 μm, morepreferred less than 20 μm and most preferred less than 15 μm.

According to one embodiment, the through holes may be laser-drilledthrough holes formed in at least two stages, one stage forming thenozzle portion and the remaining stage/-s forming the remainder of thethrough holes.

Yet, also other manufacturing methods may be used leading to a nozzleportion which is substantially cylindrical or conical with a toleranceof less than +100% of the smallest diameter, preferably less than +50%of the smallest diameter, more preferably less than +30% of the smallestdiameter and most preferred less than +15% of the smallest diameter.

Alternatively, the through holes may as well be formed in anelectroforming process. In this instant, but also using othermanufacturing methods, the through holes may have a first funnel-shapedportion at the first side and a second funnel-shaped portion at thesecond side with the nozzle portion in-between the first and the secondfunnel-shaped portions and defined between the exit opening and thelarger diameter. In this instance, the total length of the through holesmay as well be defined by the distances from the first side to the exitopening (smallest diameter) only.

In addition, it has been found that the TOR may be further increasedwhen increasing the number of through holes provided in the membrane.This may either be achieved by increasing the active perforated surfaceof the membrane and maintaining the distance of the through holesrelative to each other at the same level, or by means of reducing thedistance of the through holes relative to each other and maintaining theactive area of the membrane. In addition, these measures may as well becombined. From this perspective, it is advantageous that the membranecomprises between 200 and 8,000 through holes, preferably between 1,000and 6,000, and most preferred between 2,000 and 4,000 of the throughholes. Preferably, more than 2,000 through holes are provided. Thisfeature may as well be implemented in an aerosol generator having anozzle portion different than described herein.

Further advantages and features, which may be implemented in an aerosolgenerator as described above in isolation or in combination with otherfeatures as long as the features do not contradict each other, aredescribed in the following description of a preferred embodiment of thepresent invention. This description makes reference to the accompanyingdrawings, in which

FIG. 1 shows a cross-sectional view of a generally known aerosolgenerator;

FIG. 2 is a computer tomography (CT) picture showing a membrane having arelatively long nozzle portion;

FIG. 3 is a computer tomography (CT) picture of another membrane havinga relatively short nozzle portion;

FIG. 4 is a computer tomography (CT) picture of another membrane havinga relatively short nozzle portion;

FIG. 5 is a computer tomography (CT) picture of another membrane havinga relatively short nozzle portion.

FIG. 1 shows an aerosol generator as disclosed in WO 2001/032246 A1,which is hereby incorporated by reference in its entirety. The aerosolgenerator comprises a fluid reservoir 21 to contain the fluid,particularly a liquid, to be emitted into the mixing chamber 3 in theform of an aerosol and to be inhaled by means of the mouth piece 4through the opening 41.

The aerosol generator comprises a vibratable membrane 22 vibrated bymeans of a piezoelectric actuator 23. The vibratable membrane 22 has afirst side 24 facing the fluid container 21 and a second opposite side25 facing the mixing chamber 3. In use, the first side 24 of thevibratable membrane 22 is in contact with the fluid contained in thefluid container 21. A plurality of through holes 26 penetrating themembrane from the first side 24 to the second side 25 are provided inthe membrane 22. In use, the fluid passes from the fluid container 21through the through holes 26 from the first 24 to the second side 25when the membrane 22 is vibrated for generating the aerosol at thesecond side 25 and emitting it into the mixing chamber 3. This aerosolmay then be drawn by inhalation of a patient from the mixing chamber 3via the mouth piece 4 and its inhalation opening 41.

FIG. 2 shows a cross-sectional CT picture showing three of the throughholes 26 of such a vibratable membrane 22. The through holes 26 of thisparticular embodiment are formed by laser drilling using three stages ofdifferent process parameters, respectively. In a first stage, theportion 30 is formed. In a second stage the portion 31 is formed and ina third stage the nozzle portion 32 is formed. In this particularembodiment, the average length of the nozzle portion 32 is 26 μm,whereas the portion 31 has an average length of 51 μm. The first portion30 has an average length of 24.5 μm. As a result, the total length ofeach through hole is the sum of the length of the portion 30, theportion 31 and the nozzle portion 32, that is in this particular example101.5 μm. Thus, the ratio of the total length of each through hole 26 inthe extension direction E to the length of a respective one of thenozzle portions 32 in the extension direction E is approximately 3.9.

In the embodiment in FIG. 3, however, the first portion 30 has a lengthof 27 μm, the portion 31 a length of 55 μm and a nozzle portion a lengthof 19 μm. As a result, the total length of the through hole 26 is 101μm. Thus, the ratio of the total length of the through hole 26 to thelength of the corresponding nozzle portion 32 in this embodiment isapproximately 5.3.

In the embodiment in FIG. 4, however, the first portion 30 has a lengthof 25 μm, the portion 31 a length of 59 μm and a nozzle portion a lengthof 17 μm. As a result, the total length of the through hole 26 is 101μm. Thus, the ratio of the total length of the through hole 26 to thelength of the corresponding nozzle portion 32 in this embodiment isapproximately 5.9.

In the embodiment in FIG. 5, however, the first portion 30 has a lengthof 29.4 μm, the portion 31 a length of 55.7 μm and a nozzle portion alength of 16.3 μm. As a result, the total length of the through hole 26is 101.4 μm. Thus, the ratio of the total length of the through hole 26to the length of the corresponding nozzle portion 32 in this embodimentis approximately 6.2.

Both the vibratable membranes in FIGS. 2,3 and 5 were manufactured with6,000 through holes 26. The below table indicates the medium massdiameter (MMD) of the particles emitted at the second side of themembrane, the time required for completely emitting a certain amount ofliquid (Neb Time) as well as the TOR. The tests were performed withARIKACE™, which is a liposomal formulation of amikacine.

TABLE 1 MMD Neb TOR Number of Membrane [μm] time [min] [g/min] throughholes 26 1 (shown in FIG. 2 4.2 14.6 0.57 6,000 with a nozzle portion of26 μm) 2 (shown in FIG. 3 4.3 9.3 0.89 6,000 with a nozzle portion of 19μm) 3 (similar to FIG. 3) 4.4 13.4 0.62 3,000 4 (similar to FIG. 3) 4.411.9 0.7 3,000 5 (shown in FIG. 4 4.3 11.7 0.71 3,000 with a nozzleportion of 17 μm) 6 (shown in FIG. 5 4.3 9.3 0.90 6,000 with a nozzleportion of 16.3 μm)

The above table shows that the membrane 2 and 6 with the shorter nozzleportion provides for an increased TOR and a reduced nebulization time by5.3 minutes, that is approximately 36% less as compared to the membrane1. The above table as well shows that the difference in the MMD is notsignificant as compared to the significant difference in the TOR. Thus,by means of the present invention, the nebulization time can be reducedsignificantly, without affecting the droplet size characteristics.

In addition to the membrane shown in FIGS. 2 and 3, membranes weremanufactured having the nozzle portion further reduced but with 3,000through holes 26 only. In particular, a membrane 3 had beenlaser-drilled with a shorter nozzle portion, whereas a membrane 4 hadbeen manufactured using an even shorter nozzle portion. A furthermembrane 5 with 3,000 holes is shown in FIG. 4. From the above table, itbecomes apparent that even with 3,000 holes (membrane 3,4 and 5) areduction in the length of the nozzle portion results in an increasedTOR compared to membrane 1 with 6,000 holes. The comparison of themembrane 3 and 4 as compared to the membrane 2 further shows that acombination of a higher number of holes (6,000 as compared to 3,000) anda reduced length of the nozzle portion has the strongest effect onincreasing the TOR (membrane 2).

Further, it is advantageous to use a laser drilling process as comparedto electroforming, as the through holes as shown in FIGS. 2 and 3 aresubstantially cylindrical or conical as compared to the funnel-shapedentrance and exit of electro-formed through holes as disclosed in WO01/18280 A1. The vibration of the membrane, that is its vibrationvelocity, may be transferred to the liquid over a larger area by meansof friction when the through holes are substantially cylindrical orconical as compared to the funnel-shaped entrance and exit ofelectro-formed through holes. The liquid is then because of its owninertia ejected from the exit openings of the through holes resulting inliquid jets collapsing to form the aerosol. Because of the extremelybent surface of the holes of an electro-formed membrane, the surface orarea for transferring the energy from the membrane to the liquid isreduced. Yet, the present invention may as well be implemented inelectro-formed membranes, wherein the nozzle portion is defined by thatcontinuous portion of the through hole in the extension directionstarting from the smallest diameter of the through hole towards thefirst side until it reaches a diameter triple or preferably only twicesaid smallest diameter. In this instance, the total length of thethrough hole is preferably measured from the smallest diameter to thefirst side.

The present invention of an aerosol generator can be used for differentfluids, particularly liquids, for example for applications in themedical, pharmaceutical, diagnostic and/or analytical fields (e.g. humanand veterinary aerosol therapies with drugs, substances or activecompounds) as well as for agriculture, humidification, fragrance,hairspray, pyrotechnic, warfare agent, combustion engine, extinguishing,lubrication, adhesive, filtering, cooling, painting, printing,varnishing, coating processes, technologies and systems. Furtherexamples are in the field of cell culture, pollen, herbal, medical,chemical, physical, biological, meteorological, pesticide, fungicide,biocide, toxic, environment, and exposition aerosol applications.

Among the active compounds which may be useful for serving one of thepurposes named previously and that may be used together with the presentinvention, are, for example, substances selected from the groupconsisting of anti-inflammatory compounds, anti-infective agents,antiseptics, prostaglandins, endothelin receptor agonists,phosphodiesterase inhibitors, beta-2-sympathicomimetics, decongestants,vasoconstrictors, anticholinergics, immunomodulators, mucolytics,anti-allergic drugs, antihistaminics, mast-cell stabilizing agents,tumor growth inhibitory agents, wound healing agents, localanaesthetics, antioxidants, oligonucleotides, peptides, proteins,vaccines, vitamins, plant extracts, cholinesterase inhibitors,vasoactive intestinal peptide, serotonin receptor antagonists, andheparins, glucocorticoids, anti-allergic drugs, antioxidants, vitamins,leucotriene antagonists, anti-infective agents, antibiotics,antifungals, antivirals, mucolytics, decongestants, antiseptics,cytostatics, immunomodulators, vaccines, wound healing agents, localanaesthetics, oligonucleotides,xanthin derived agents, peptides,proteins and plant extracts. Such compound may be used in the form of asuspension, a solution, a colloidal formulation (i.e. liposomal), etc.

Examples of potentially useful anti-inflammatory compounds areglucocorticoids and non-steroidal anti-inflammatory agents such asbetamethasone, beclomethasone, budesonide, ciclesonide, dexamethasone,desoxymethasone, fluocinolone acetonide, fluocinonide, flunisolide,fluticasone, icomethasone, rofleponide, triamcinolone acetonide,fluocortin butyl, hydrocortisone, hydroxycortisone-17-butyrate,prednicarbate, 6-methylprednisolone aceponate, mometasone furoate,dehydroepiandrosterone-sulfate (DHEAS), elastane, prostaglandin,leukotriene, bradykinin antagonists, non-steroidal anti-inflammatorydrugs (NSAIDs), such as ibuprofen including any pharmaceuticallyacceptable salts, esters, isomers, stereoisomers, diastereomers,epimers, solvates or other hydrates, prodrugs, derivatives, or any otherchemical or physical forms of active compounds comprising the respectiveactive moieties.

Examples of anti-infective agents, whose class or therapeutic categoryis herein understood as comprising compounds which are effective againstbacterial, fungal, and viral infections, i.e. encompassing the classesof antimicrobials, antibiotics, antifungals, antiseptics, andantivirals, are

-   -   penicillins, including benzylpenicillins (penicillin-G-sodium,        clemizone penicillin, benzathine penicillin G),        phenoxypenicillins (penicillin V, propicillin),        aminobenzylpenicillins (ampicillin, amoxycillin, bacampicillin),        acylaminopenicillins (azlocillin, mezlocillin, piperacillin,        apalcillin), carboxypenicillins (carbenicillin, ticarcillin,        temocillin), isoxazolyl penicillins (oxacillin, cloxacillin,        dicloxacillin, flucloxacillin), and amidine penicillins        (mecillinam);    -   cephalosporins, including cefazolins (cefazolin, cefazedone);        cefuroximes (cefuroxim, cefamandole, cefotiam), cefoxitins        (cefoxitin, cefotetan, latamoxef, flomoxef), cefotaximes        (cefotaxime, ceftriaxone, ceftizoxime, cefmenoxime),        ceftazidimes (ceftazidime, cefpirome, cefepime), cefalexins        (cefalexin, cefaclor, cefadroxil, cefradine, loracarbef,        cefprozil), and cefiximes (cefixime, cefpodoxim proxetile,        cefuroxime axetil, cefetamet pivoxil, cefotiam hexetil),        loracarbef, cefepim, clavulanic acid/amoxicillin, Ceftobiprole;    -   synergists, including beta-lactamase inhibitors, such as        clavulanic acid, sulbactam, and tazobactam;    -   carbapenems, including imipenem, cilastin, meropenem, doripenem,        tebipenem, ertapenem, ritipenam, and biapenem;    -   monobactams, including aztreonam;    -   aminoglycosides, such as apramycin, gentamicin, amikacin,        isepamicin, arbekacin, tobramycin, netilmicin, spectinomycin,        streptomycin, capreomycin, neomycin, paromoycin, and kanamycin;    -   macrolides, including erythromycin, clarythromycin,        roxithromycin, azithromycin, dithromycin, josamycin, spiramycin        and telithromycin;    -   gyrase inhibitors or fluroquinolones, including ciprofloxacin,        gatifloxacin, norfloxacin, ofloxacin, levofloxacin, perfloxacin,        lomefloxacin, fleroxacin, garenoxacin, clinafloxacin,        sitafloxacin, prulifloxacin, olamufloxacin, caderofloxacin,        gemifloxacin, balofloxacin, trovafloxacin, and moxifloxacin;    -   tetracyclins, including tetracyclin, oxytetracyclin,        rolitetracyclin, minocyclin, doxycycline, tigecycline and        aminocycline;    -   glycopeptides, inicuding vancomycin, teicoplanin, ristocetin,        avoparcin, oritavancin, ramoplanin, and peptide 4;    -   polypeptides, including plectasin, dalbavancin, daptomycin,        oritavancin, ramoplanin, dalbavancin, telavancin, bacitracin,        tyrothricin, neomycin, kanamycin, mupirocin, paromomycin,        polymyxin B and colistin;    -   sulfonamides, including sulfadiazine, sulfamethoxazole,        sulfalene, co-trimoxazole, co-trimetrol, co-trimoxazine, and        co-tetraxazine;    -   azoles, including clotrimazole, oxiconazole, miconazole,        ketoconazole, itraconazole, fluconazole, metronidazole,        tinidazole, bifonazol, ravuconazol, posaconazol, voriconazole,        and ornidazole and other antifungals including flucytosin,        griseofulvin, tolnaftat, naftifin, terbinafin, amorolfin,        ciclopiroxolamin, echinocandins, such as micafungin,        caspofungin, anidulafungin;    -   nitrofurans, including nitrofurantoin and nitrofuranzone;    -   polyenes, including amphotericin B, natamycin, nystatin,        flucocytosine;flucytosine    -   other antibiotics, including tithromycin, lincomycin,        clindamycin, oxazolidinones (linzezolids), ranbezolid,        streptogramine A+B, pristinamycin A+B, Virginiamycin A+B,        dalfopristin /quinupristin (Synercid), chloramphenicol,        ethambutol, pyrazinamid, terizidon, dapson, prothionamid,        fosfomycin, fucidinic acid, rifampicin, isoniazid, cycloserine,        terizidone, ansamycin, lysostaphin, iclaprim, mirocin B17,        cierocidin, filgrastim, and pentamidine;    -   antivirals, including aciclovir, ganciclovir, birivudin,        valaciclovir, zidovudine, didanosin, thiacytidin, stavudin,        lamivudin, zalcitabin, ribavirin, nevirapirin, delaviridin,        trifluridin, ritonavir, saquinavir, indinavir, foscarnet,        amantadin, podophyllotoxin, vidarabine, tromantadine, and        proteinase inhibitors, siRNA-based drugs;    -   antiseptics, including acridine derivatives, iodine-povidone,        benzoates, rivanol, chlorhexidine, quarternary ammonium        compounds, cetrimides, biphenylol, clorofene, and octenidine;    -   plant extracts or ingredients, such as plant extracts from        chamomile, hamamelis, echinacea, calendula, thymian, papain,        pelargonium, pine trees, essential oils, myrtol, pinen, limonen,        cineole, thymol, mental, camphor, tannin, alpha-hederin,        bisabolol, lycopodin, vitapherole;    -   wound healing compounds including dexpantenol, allantoin,        vitamins, hyaluronic acid, alpha-antitrypsin, anorganic and        organic zinc salts/compounds, salts of bismuth and selen    -   interferones (alpha, beta, gamma), tumor necrosis factors,        cytokines, interleukines;    -   immunmodulators including methotrexat, azathioprine,        cyclosporine, tacrolimus, sirolimus, rapamycin, mofetil;        mofetil-mycophenolate.    -   cytostatics and metastasis inhibitors;    -   alkylants, such as nimustine, melphalane, carmustine, lomustine,        cyclophosphosphamide, ifosfamide, trofosfamide, chlorambucil,        busulfane, treosulfane, prednimustine, thiotepa;    -   antimetabolites, e.g. cytarabine, fluorouracil, methotrexate,        mercaptopurine, tioguanine;    -   alkaloids, such as vinblastine, vincristine, vindesine;    -   antibiotics, such as alcarubicine, bleomycine, dactinomycine,        daunorubicine, doxorubicine, epirubicine, idarubicine,        mitomycine, plicamycine;    -   complexes of transition group elements (e.g. Ti, Zr, V, Nb, Ta,        Mo, W, Pt) such as carboplatinum, cis-platinum and metallocene        compounds such as titanocendichloride;    -   amsacrine, dacarbazine, estramustine, etoposide, beraprost,        hydroxycarbamide, mitoxanthrone, procarbazine, temiposide;    -   paclitaxel, gefitinib, vandetanib, erlotinib,        poly-ADP-ribose-polymerase (PRAP) enzyme inhibitors,        banoxantrone, gemcitabine, pemetrexed, bevacizumab, ranibizumab.        Examples of potentially useful mucolytics are DNase,        P2Y2-agonists (denufosol), drugs affecting chloride and sodium        permeation, such as        N-(3,5-Diamino-6-chloropyrazine-2-carbony)-N′-{4-[4-(2,3-dihydroxypropoxy)-phenyl]butyl}guanidine        methanesulfonate (PARION 552-02), heparinoids, guaifenesin,        acetylcysteine, carbocysteine, ambroxol, bromhexine, tyloxapol,        lecithins, myrtol, and recombinant surfactant proteins.

Examples of potentially useful vasoconstrictors and decongestants whichmay be useful to reduce the swelling of the mucosa are phenylephrine,naphazoline, tramazoline, tetryzoline, oxymetazoline, fenoxazoline,xylometazoline, epinephrine, isoprenaline, hexoprenaline, and ephedrine.

Examples of potentially useful local anaesthetic agents includebenzocaine, tetracaine, procaine, lidocaine and bupivacaine.

Examples of potentially useful antiallergic agents include theafore-mentioned glucocorticoids, cromolyn sodium, nedocromil, cetrizin,loratidin, montelukast, roflumilast, ziluton, omalizumab, heparinoidsand other antihistamins, including azelastine, cetirizin, desloratadin,ebastin, fexofenadin, levocetirizin, loratadin.

Examples of potentially useful anticholinergic agents includeipratropium bromide, tiotropium bromide, oxitropium bromide,glycopyrrolate

Examples of potentially useful beta-2-sympathicomimetic agents includesalbutamol, fenoterol, formoterol, isoproterenol, metaproterenol,salmeterol, terbutaline, clenbuterol, isoetarine, pirbuterol,procaterol, ritodrine,

Examples of xanthin derived agents include theophylline, theobromine,caffeine

This list, however, is not exhaustive.

1. An aerosol generator for generating an aerosol from a fluid,comprising: a vibratable membrane having a first side for being incontact with the fluid and an opposite second side, the membrane havinga plurality of through holes penetrating the membrane in an extensiondirection from the first side to the second side, whereby the fluidpasses the through holes from the first side to the second side when themembrane is vibrated for generating the aerosol at the second side, eachthrough hole (26) having along its extension direction a smallestdiameter, a larger diameter that is larger than the smallest diameterand defined by that diameter that is closest to twice said smallestdiameter, each through hole having a nozzle portion defined by thatcontinuous portion of the through hole in the extension directioncomprising the smallest diameter of the through hole and bordered by thelarger diameter of the through hole, wherein the ratio of the totallength of each through hole in the extension direction to the length ofa respective one of said nozzle portions in the extension direction isat least
 4. 2. The aerosol generator according to claim 1, wherein oneend of the nozzle portion terminates flush with the second side.
 3. Theaerosol generator as defined in claim 1, wherein the smallest diameteris located at that end of the nozzle portion in the extension directionadjacent to the second side.
 4. The aerosol generator as defined inclaim 1, wherein the smallest diameter is smaller than 4.5 μm.
 5. Theaerosol generator as defined in claim 1, wherein the total length of thethrough holes in the extension direction is at least 50 μm.
 6. Theaerosol generator as defined in claim 1, wherein the length of thenozzle portion is less than 25 μm.
 7. The aerosol generator as definedin claim 1, wherein the through holes are laser drilled through holesformed in at least two stages, one stage forming the nozzle portion andthe remaining stage/-s forming the remainder of the through holes. 8.The aerosol generator as defined in claim 1, wherein the nozzle portionis substantially cylindrical or conical with a tolerance of less than100% of the smallest diameter.
 9. The aerosol generator as defined inclaim 1, wherein the through holes have a first funnel-shaped portion atthe first side and a second funnel-shaped portion at the second sidewith the nozzle portion between the first and second funnel-shapedportions.
 10. The aerosol generator as defined in claim 1, wherein themembrane comprises between 200 and 8,000 holes.
 11. The aerosolgenerator as defined in claim 1, wherein the aerosol generator isconfigured to generate a medical and/or diagnostic aerosol from thefluid for aerosol application and/or inhalation therapy.
 12. The aerosolgenerator as defined in claim 1, wherein the ratio of the total lengthof each through hole in the extension direction to the length of arespective one of said nozzle portions in the extension direction isless than
 10. 13. The aerosol generator according to claim 1, whereinthe ratio of the total length of each through hole in the extensiondirection to the length of a respective one of said nozzle portions inthe extension direction is at least 4.5.
 14. The aerosol generatoraccording to claim 1, wherein the ratio of the total length of eachthrough hole in the extension direction to the length of a respectiveone of said nozzle portions in the extension direction is equal to orlarger than
 5. 15. The aerosol generator as defined in claim 1, whereinthe total length of the through holes in the extension direction is atleast 70 μm.
 16. The aerosol generator as defined in claim 1, whereinthe total length of the through holes in the extension direction is atleast 90 μm.
 17. The aerosol generator as defined in claim 1, whereinthe length of the nozzle portion is less than 20 μm.
 18. The aerosolgenerator as defined in claim 1, wherein the length of the nozzleportion is less than 15 μm.
 19. The aerosol generator as defined inclaim 1, wherein the nozzle portion is substantially cylindrical orconical with a tolerance of less than +50% of the smallest diameter. 20.The aerosol generator as defined in claim 1, wherein the nozzle portionis substantially cylindrical or conical with a tolerance of less than+30% of the smallest diameter.
 21. The aerosol generator as defined inclaim 1, wherein the nozzle portion is substantially cylindrical orconical with a tolerance of less than +15% of the smallest diameter. 22.The aerosol generator as defined in claim 1, wherein the ratio of thetotal length of each through hole in the extension direction to thelength of a respective one of said nozzle portions in the extensiondirection is less than
 8. 23. The aerosol generator as defined in claim1, wherein the ratio of the total length of each through hole in theextension direction to the length of a respective one of said nozzleportions in the extension direction is equal to or less than 6.5.
 24. Anaerosol generator for generating an aerosol from a fluid, comprising: avibratable membrane having a first side for being in contact with thefluid and an opposite second side, the membrane having a plurality ofthrough holes penetrating the membrane in an extension direction fromthe first side to the second side, whereby the fluid passes the throughholes from the first side to the second side when the membrane isvibrated for generating the aerosol at the second side, each throughhole having along its extension direction a smallest diameter, a largerdiameter that is larger than the smallest diameter and defined by thatdiameter that is closest to triple said smallest diameter, each throughhole having a nozzle portion defined by that continuous portion of thethrough hole in the extension direction comprising the smallest diameterof the through hole and bordered by the larger diameter of the throughhole, wherein the ratio of the total length of each through hole in theextension direction to the length of a respective one of said nozzleportions in the extension direction is at least
 4. 25. The aerosolgenerator according to claim 24, wherein the ratio of the total lengthof each through hole in the extension direction to the length of arespective one of said nozzle portions in the extension direction is atleast 4.5.
 26. The aerosol generator according to claim 24, wherein theratio of the total length of each through hole in the extensiondirection to the length of a respective one of said nozzle portions inthe extension direction is equal to or larger than
 5. 27. The aerosolgenerator as defined in claim 24, wherein the ratio of the total lengthof each through hole in the extension direction to the length of arespective one of said nozzle portions in the extension direction isless than
 8. 28. The aerosol generator as defined in claim 24, whereinthe ratio of the total length of each through hole in the extensiondirection to the length of a respective one of said nozzle portions inthe extension direction is equal to or less than 6.5.